Five-year overall survival (OS) in children with diffuse, intrinsic brainstem glioma (BSG), ependymoma (EP) and medulloblastoma (MB) are 25%, 50% and 60% respectively (1-4), and the outcome for patients with recurrent disease is dismal. Thus, achieving cure for all children with high grade gliomas (HGG), MB and EP remains a major goal of pediatric neuro-oncology. We have previously demonstrated that ERBB2 and ERBB4 oncogenes are highly expressed in aggressive forms of MB and EP (5,6) and ERBB1 is amplified and over-expressed in BSG (7). Aberrant ERBB signaling has been implicated in proliferation, mitogenesis, inhibition of apoptosis, cell migration, angiogenesis, metastases and differentiation (8-15) and is known to play a key role in the development and progression of certain adult adenocarcinomas (e.g. breast) and glial tumors(16). We propose ERBB receptors as a potential new therapeutic target for pediatric HGG, MB, and EP. Our pre-clinical studies with a variety of ERBB inhibitors have demonstrated in vitro and in vivo activity of these agents in MB, and EP (6; 17; 18) One such dual ERBB1/ERBB2 tyrosine kinase inhibitor with promising antitumor activity is Lapatinib. In this application, we propose to build on our pre-clinical and clinical studies and investigate the molecular activity and therapeutic potential of Lapatinib, in children with recurrent or refractory MB, HGG, and EP. The primary aims of this proposal are a) to determine the maximum tolerated dose (MTD), dose limiting toxicities (DLT) and pharmacokinetics (PK) of Lapatinib in children with recurrent CNS malignancies in a phase I study; b) to conduct a molecular biology/pharmacodynamic (PD) study in which patients with recurrent or refractory MB, EP, and HGG undergoing tumor resection will be randomized to pre-resection treatment with lapatinib or no treatment. This study will allow the estimation of ERBB expression, receptor signaling inhibition and drug concentration in tumor at the MTD, and c) to assess the sustained response rate in patients with recurrent MB/PNET, EP, or HGG in a phase II study. The trial will be conducted through the Pediatric Brain Tumor Consortium. These data will be used in the rational design of future phase I combination or frontline studies to improve the outcome in children with these poor prognosis tumors. [unreadable] [unreadable]